ErbB-2, the preferred heterodimerization partner of all ErbB receptors, is a mediator of lateral signaling

EMBO J. 1997 Apr 1;16(7):1647-55. doi: 10.1093/emboj/16.7.1647.


We have analyzed ErbB receptor interplay induced by the epidermal growth factor (EGF)-related peptides in cell lines naturally expressing the four ErbB receptors. Down-regulation of cell surface ErbB-1 or ErbB-2 by intracellular expression of specific antibodies has allowed us to delineate the role of these receptors during signaling elicited by: EGF and heparin binding EGF (HB-EGF), ligands of ErbB-1; betacellulin (BTC), a ligand of ErbB-1 and ErbB-4; and neu differentiation factor (NDF), a ligand of ErbB-3 and ErbB-4. Ligand-induced ErbB receptor heterodimerization follows a strict hierarchy and ErbB-2 is the preferred heterodimerization partner of all ErbB proteins. NDF-activated ErbB-3 or ErbB-4 heterodimerize with ErbB-1 only when no ErbB-2 is available. If all ErbB receptors are present, NDF receptors preferentially dimerize with ErbB-2. Furthermore, EGF- and BTC-induced activation of ErbB-3 is impaired in the absence of ErbB-2, suggesting that ErbB-2 has a role in the lateral transmission of signals between other ErbB receptors. Finally, ErbB-1 activated by all EGF-related peptides (EGF, HB-EGF, BTC and NDF) couples to SHC, whereas only ErbB-1 activated by its own ligands associates with and phosphorylates Cbl. These results provide the first biochemical evidence that a given ErbB receptor has distinct signaling properties depending on its dimerization.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Betacellulin
  • Calcium-Calmodulin-Dependent Protein Kinases / metabolism
  • Dimerization
  • Down-Regulation
  • Epidermal Growth Factor / metabolism
  • Epidermal Growth Factor / pharmacology
  • ErbB Receptors / isolation & purification
  • ErbB Receptors / metabolism
  • Female
  • Glycoproteins / metabolism
  • Glycoproteins / pharmacology
  • Growth Substances / metabolism
  • Growth Substances / pharmacology
  • Humans
  • Intercellular Signaling Peptides and Proteins*
  • Kinetics
  • Models, Biological
  • Models, Structural
  • Neuregulins
  • Receptor, ErbB-2 / biosynthesis
  • Receptor, ErbB-2 / metabolism*
  • Recombinant Proteins / metabolism
  • Recombinant Proteins / pharmacology
  • Signal Transduction*
  • Transfection
  • Tumor Cells, Cultured
  • Vulvar Neoplasms


  • BTC protein, human
  • Betacellulin
  • Glycoproteins
  • Growth Substances
  • Intercellular Signaling Peptides and Proteins
  • Neuregulins
  • Recombinant Proteins
  • Epidermal Growth Factor
  • ErbB Receptors
  • Receptor, ErbB-2
  • Calcium-Calmodulin-Dependent Protein Kinases